Phencyclidine induction of the hsp70 stress gene in injured pyramidal neurons is mediated via multiple receptors and voltage gated calcium channels

Sharp, Frank R.; Butman, M.; Koistinaho, Jari; Aardalen, K.; Näkki, Riitta; Massa, Stephen M.; Swanson, Raymond A.; Sagar, Stephen M.

doi:10.1016/0306-4522(94)90345-x

Cited by 84 publications

(57 citation statements)

References 102 publications

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“…Clozapine blocks Hsp70 induction in pyramidal neurons produced by PCP (ED50F1 mg/kg; Sharp et al, 1994b). Moreover, clozapine (ED50F2.8 mg/kg), olanzapine (ED50F0.6 mg/kg), and fluperlapine (ED50F2.4 mg/ kg) block formation of vacuoles in pyramidal neurons in retrosplenial cortex produced by systemic MK-801 (0.5 mg/ kg) (Farber et al, 1993(Farber et al, , 1996Olney and Farber, 1994).…”

Section: Discussionmentioning

confidence: 99%

“…Haloperidol blocked the injury to retrosplenial cortex produced by NMDA-receptor antagonists in rats (Sharp et al, 1992(Sharp et al, , 1993(Sharp et al, , 1994a. These findings prompted studies of atypical antipsychotics, including clozapine and olanzapine, which also blocked the cortical injury produced by NMDA antagonists in rodents (Farber et al, 1993(Farber et al, , 1996Olney and Farber, 1994;Sharp et al, 1994b). Therefore, it appeared as though drugs that decrease psychosis in people all block the limbic cortical injury produced by NMDAreceptor antagonists in rodents.…”

Section: Introductionmentioning

confidence: 99%

“…Indeed, the Src antagonist protects against MK-801-mediated injury, which might suggest a role for Src kinases mediating PCP/ketamine/MK-801 behaviors in humans. Since some drugs block MK-801-mediated injury that are not antipsychotics, including calcium channel blockers and antimuscarinics and selective serotonin reuptake antagonists (Sharp et al, 1994b;Tomitaka et al, 2000a), it is not clear whether Src antagonists might or might not affect psychosis.…”

Section: Introductionmentioning

confidence: 99%

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Atypical Antipsychotics and a Src Kinase Inhibitor (PP1) Prevent Cortical Injury Produced by the Psychomimetic, Noncompetitive NMDA Receptor Antagonist MK-801

Dickerson

Sharp

2005

Neuropsychopharmacol

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Noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonists such as phencyclidine, ketamine, and MK-801 produce schizophrenia-like psychosis in humans. The same NMDA antagonists injure retrosplenial cortical neurons in adult rats. We examined the effects of atypical antipsychotics and an inhibitor of nonreceptor tyrosine kinase pp60 (Src) on the cortical injury produced by MK-801. An atypical antipsychotic (either clozapine, ziprasidone, olanzapine, quetiapine, or risperidone) or vehicle was administered to adult female Sprague-Dawley rats. PP1 (Src inhibitor), PP3 (nonfunctional analog of PP1) or vehicle (DMSO) was administered to another group of animals. After pretreatment, animals were injected with MK-801, killed 24 h after the MK-801, and injury to retrosplenial cortex assessed by neuronal Hsp70 protein expression. All atypical antipsychotics examined significantly attenuated MK-801-induced cortical damage. PP1 protected compared to vehicle, whereas PP3 did not protect. The ED50s (decrease injury by 50%) were as follows: PP1 o0.1 mg/kg; olanzapine 0.8 mg/kg; risperdal 1 mg/kg; clozapine 3 mg/kg; ziprasidone 32 mg/kg; and quetiapine 45 mg/kg. The data show that the atypical antipsychotics tested as well as a Src kinase inhibitor prevent the injury produced by the psychomimetic MK-801, and the potency of the atypical antipsychotics for preventing cortical injury was roughly similar to the potency of these drugs for treating psychosis in patients.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Atypical Antipsychotics and a Src Kinase Inhibitor (PP1) Prevent Cortical Injury Produced by the Psychomimetic, Noncompetitive NMDA Receptor Antagonist MK-801

Dickerson

Sharp

2005

Neuropsychopharmacol

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“…These effects are characterized by reversible intracellular vacuolization (Olney et al 1989) and induction of mRNAs for c-fos (Dragunow and Faull 1990;Hughes et al 1993;Näkki et al 1996), heat shock protein 70 (HSP70) (Sharp et al 1991(Sharp et al , 1994Näkki et al 1995), and brain-derived neurotrophic factor (BDNF) Hughes et al 1993). Induction of cfos and BDNF is typically observed in activated neurons and we therefore tentatively call these effects "ex- citatory" to distinguish them from the prevention of excitation, which is the typical effect of NMDA receptor antagonists in other brain areas.…”

Section: We Have Characterized Excitatory Effects Of Non-competitive mentioning

confidence: 99%

Excitatory Actions of NMDA Receptor Antagonists in Rat Entorhinal Cortex and Cultured Entorhinal Cortical Neurons

Väisänen

Lindén

Lakso

et al. 1999

Neuropsychopharmacology

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We have characterized excitatory effects of non-competitive NMDA receptor antagonists MK-801, PCP, and ketamine in the rat entorhinal cortex and in cultured primary entorhinal cortical neurons using expression of immediate early gene c-fos as an indicator. NMDA receptor antagonists produced a strong and dose-dependent increase in c-fos mRNA and protein expression confined to neurons in the layer III of the caudal entorhinal cortex. Induction of c-fos mRNA is delayed and it is inhibited by antipsychotic drugs. Cultured entorhinal neurons are killed by high doses of MK-801 and PCP but c-fos expression is not induced in these neurons indicating that this in vitro model does not fully replicate the in vivo effects of PCP-like drugs in the entorhinal cortex. Excitatory effects of the NMDA receptor antagonists may be connected with the psychotropic side effects of these drugs and might become a useful modelNMDA receptor antagonists, such as phencyclidine, ketamine, and MK-801 (dizocilpine) produce in humans psychotogenic side effects which clinically closely resemble schizophrenia and are characterized by distorted body image, hallucinations, vivid dreams, and delirium (Johnson and Jones 1990;Javitt and Zukin 1991). Ketamine also frequently induces psychotic "emergence reactions" in adults (Krystal et al. 1994). Because of these parallels between the psychotomimetic state produced by the NMDA receptor antagonists and schizophrenia, PCP-induced psychosis has widely been used as an experimental model of schizophrenia (Javitt and Zukin 1991).In a series of pioneering studies, Olney and coworkers demonstrated that NMDA receptor antagonists produce reversible neurotoxic effects in neurons in the posterior cingulate and retrosplenial cortices (RSC) of rat brain (Olney et al. 1989(Olney et al. , 1991 Farber 1995a, 1995b). These effects are characterized by reversible intracellular vacuolization (Olney et al. 1989) and induction of mRNAs for c-fos (Dragunow and Faull 1990;Hughes et al. 1993;Näkki et al. 1996), heat shock protein 70 (HSP70) (Sharp et al. 1991(Sharp et al. , 1994Näkki et al. 1995), and brain-derived neurotrophic factor (BDNF) Hughes et al. 1993). Induction of cfos and BDNF is typically observed in activated neurons and we therefore tentatively call these effects "ex- citatory" to distinguish them from the prevention of excitation, which is the typical effect of NMDA receptor antagonists in other brain areas. These excitatory actions may be connected with the psychotomimetic side effects produced by PCP-like drugs Farber 1995a, 1995b). We have previously observed that MK-801 increases mRNA for BDNF not only in the retrosplenial cortex but also in the entorhinal cortex (EC) . EC is the input and output station of the information going to and coming from the hippocampus (Jones 1993;Amaral and Witter 1995). It is thought that the EC-hippocampus loop is very important in the processing of sensory information and defects in its normal function might produce cognitive disturbances (Jones 1993). Therefore, neurons i...

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“…71 PCP impairs learning and memory performance in rats. 23,[72][73][74] PCP also induces neurodegeneration [75][76][77] and apoptosis 78 in rat brain, and can decrease Bcl-X L and increase Bax in the frontal cortex of perinatal rats. 79 A single dose (50 mg/kg) of PCP causes reference spatial memory impairment in the radial maze task and a decrease in the ratio of Bcl-X L (an anti-apoptotic Bcl-2 family member) to Bax (a pro-apoptotic analogue) in the posterior cingulate cortex in rats.…”

Section: Effect Of Quetiapine On Phencyclidine-induced Memory Impairmmentioning

confidence: 99%

Neuroprotective effect of atypical antipsychotics in cognitive and non-cognitive behavioral impairment in animal models

Kong

Tan³

et al. 2009

Cell Adhesion & Migration

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Phencyclidine induction of the hsp70 stress gene in injured pyramidal neurons is mediated via multiple receptors and voltage gated calcium channels

Cited by 84 publications

References 102 publications

Atypical Antipsychotics and a Src Kinase Inhibitor (PP1) Prevent Cortical Injury Produced by the Psychomimetic, Noncompetitive NMDA Receptor Antagonist MK-801

Atypical Antipsychotics and a Src Kinase Inhibitor (PP1) Prevent Cortical Injury Produced by the Psychomimetic, Noncompetitive NMDA Receptor Antagonist MK-801

Excitatory Actions of NMDA Receptor Antagonists in Rat Entorhinal Cortex and Cultured Entorhinal Cortical Neurons

Neuroprotective effect of atypical antipsychotics in cognitive and non-cognitive behavioral impairment in animal models

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